Deciphering the effect of phytosterols on Alzheimer’s disease and Parkinson’s disease: the mediating role of lipid profiles

Abstract Background Studies have suggested that blood circulating phytosterols, plant-derived sterols analogous to cholesterol, were associated with blood lipid levels and the risk of Alzheimer’s disease (AD) and Parkinson’s disease (PD). This Mendelian randomization (MR) study is performed to determine the causal effect of circulating phytosterols on AD and PD and evaluate the mediation effect of blood lipids. Methods Leveraging genome-wide association studies summary-level data for phytosterols, blood lipids, AD, and PD, univariable and multivariable MR (MVMR) analyses were conducted. Four types of phytosterols (brassicasterol, campesterol, sitosterol, and stigmasterol), three blood lipids parameters (high-density lipoprotein cholesterol [HDL-C], non-HDL-C, and triglyceride), two datasets for AD and PD were used. Inverse-variance weighted method was applied as the primary analysis, and false discovery rate method was used for adjustment of multiple comparisons. Results Using the largest AD dataset, genetically proxied higher levels of stigmasterol (OR = 0.593, 95%CI = 0.431–0.817, P = 0.004) and sitosterol (OR = 0.864, 95%CI = 0.791–0.943, P = 0.004) significantly correlated with a lower risk of AD. No significant associations were observed between all four types of phytosterols levels and PD. MVMR estimates showed that the above causal associations were missing after integrating the blood lipids as exposures. Sensitivity analyses confirmed the robustness of these associations, with no evidence of pleiotropy and heterogeneity. Conclusion The study supports a potential beneficial role of blood stigmasterol and sitosterol in reducing the risk of AD, but not PD, which is dependent on modulating blood lipids. These insights highlight circulating stigmasterol and sitosterol as possible biomarkers and therapeutic targets for AD.